A re-appraisal of the nature of the atropine-resistant contraction to electrical field stimulation in the human isolated detrusor muscle

Abstract

We investigated whether in human isolated detrusor strips the atropine-resistant contractile response to electrical field stimulation was mediated by ATP (or a related purine), as previously shown in the urinary bladder of other mammalian species. Electrical stimulation (1-50 Hz for 5 s at 1 min intervals, 0.1 ms pulse width, 60 V) elicited reproducible, frequency-dependent twitch contractions, which were markedly reduced by atropine (10 microM). Tetrodotoxin (TTX: 1 microM) inhibited contractile responses to a similar degree. When applied together, atropine and TTX caused an inhibition which was superimposable to that caused by either drug alone. The TTX-resistant contractions were totally unaffected by omega-conotoxin GVIA (omega-CTX: 0.1 microM). The atropine-resistant contractions were unaffected by the P2-purinoceptor antagonists suramin (300 microM) and PPADS (30 microM), at concentrations which virtually suppressed the contractile response induced by applied ATP (10 microM(-1) mM). As previously described, antagonism of the ATP-induced contractions by suramin (30, 100, 300 microM) and PPADS (3, 10, 30 microM) was insurmountable, with apparent 'pA2' values (calculated at the lowest antagonist concentrations) of 4.9 and 5.2, respectively. It is concluded that, under our experimental conditions, the non-cholinergic (atropine-resistant) component of the excitatory transmission in the human detrusor is not mediated by neural release of ATP, in spite of the presence of excitatory P2-purinoceptors on the effector cells. The TTX- and omega-CTX-resistant, non-cholinergic component might be related to the release of unknown transmitter(s) through a mechanism independent of both Na+- and N-type Ca2+-channels. More likely, the atropine-resistant component may reflect direct smooth muscle excitation since the human detrusor has a very short chronaxie (Sibley 1984).

Purinergic signalling in the urinary tract in health and disease

“…The presence of an atropine-resistant nerve component in the human bladder has been controversial, although most authors did find a small component, usually less than 5 % in healthy bladder [31,50,166,262,296,371,446,462,518,583,611,620,631,652]. One early report suggested that the NANC component in the human female bladder was greater than in the male bladder, amounting to about 50 % of the nervemediated contractile response of the bladder [163].…”

“…One paper claimed that the atropine-resistant component of excitatory transmission in the human bladder was not mediated by neural release of ATP in spite of the presence of P2 receptors in the effector cells [652].…”

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

“…This may be taken as indirect evidence of changes in the cholinergic functions of the bladder, since normally the atropine-resistant component is almost negligible (Andersson, 1993;Tagliani et al, 1997;. Alternatively, there may also be an up-regulation of the nonadrenergic, noncholinergic (NANC) component of contraction (see Section III.A.7.).…”

“…Sibley (1984) verified the occurrence of atropine resistance in hypertrophic bladder muscle, but also showed that the atropine-resistant response was resistant to TTX, suggesting that it was not nerve mediated, but that it was caused by direct muscle stimulation. Tagliani et al (1997) concluded, based on their results, that the atropine-resistant component may reflect direct smooth muscle excitation, since the human detrusor has a very short chronaxie. In contrast, Smith and Chapple (1994) showed that the NANC response from overactive, obstructed bladders was eliminated by TTX.…”

β-NAD is a novel nucleotide released on stimulation of nerve terminals in human urinary bladder detrusor muscle

“…ATP has been determined as a parasympathetic cotransmitter in numerous species (11) as well as a primary activator of afferent sensory nerves during bladder distension (4,14). Interestingly, while the purinergic component of neurally evoked contractions in normal human bladder is almost negligible (4,32), the role of ATP in the human bladder enhances significantly with aging (35) and in pathological conditions including neurogenic bladder, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis (2,23,28,29), suggesting that endogenous nucleotides may have special roles in bladder dysfunctions.…”